The Lung From a Pharmacology Perspective Flashcards
What receptors do drugs that act on the autonomic nervous system to prevent bronchospasm act on?
• is the PNS or SNS dominant? why?
- ß2-adrenergic agonists
- Muscarinic Antagonists
• PNS is dominant in the respiratory tract because it contains receptors that act directly on the bronchial smooth muscle. SNS drugs do not.
What cells do the adrenergic receptors in the lung act on?
- Epithelial Cells
- Mast Cells
- Type II alveolar Cells
M1 Receptors:
• where are they located?
• What do they do?
Location:
• M1 receptors are located on the POST-GANGLIONIC membrane to transduce vagal signal to BOTH:
1. Submucosal Glands
2. Airway Smooth muscle
***M1’s are also responsible for increased glandular secretions in the nasal mucosa
M2 Receptors:
• Where are they located?
• What do they do?
Location:
• M2’s are INHIBITORY Autoreceptors on the PRE-SYNAPTIC membrane of POST-GANGLIONIC FIBERS
• ALSO are found on AIRWAY SMOOTH MUSCLE where they oppose the increase in c-AMP caused by ß2 adrenergic stimulation
M3 Receptors:
• Where are they located?
• What do they do?
Location:
• Bronchial smooth muscle - Bronchoconstriction
•Submucosal Glands - Mucus secretion
What would be the consequence of administering a drug that antagonizes both M2 and M3 receptors?
• Name two drugs that do this.
M2 antagonism:
• tends to enhance PNS effects because there is no off signal with the Ach M2 heteroreceptor
• would help to relax tense bronchi
M3 antagonism:
• tends to attenuate PNS effects because it turns off mucous secretion and smooth muscle contraction
2 drugs:
•Atropine
• Ipratropium
What muscarinic antagonist blocks M1 and M3 receptors equally well?
Tiotropium
What are some 1st generation Antihistamines that may cause drying of secretions in the lungs?
- Chlorpheniramine
- Doxylamine
- Diphenhydramine
What effect would acetylcholinesterase inhibitors have on the lungs? Why?
• Name two.
- Edrophonium
- Neostigmine
=> treat myasthenia gravis
At what stage in the bronchospastic response should SNS drugs be given?
• do these drugs antagonize or agonize receptors?
SNS drugs:
• AGONISTS should be given EARLY in the bronchospastic response otherwise they wont be effective
• Albuterol is the example of such a drug
What is the risk of taking a ß2 agonist?
• May produce bronchoconstriction by increasing the PNS tone
What is the effect of ß2 stimulation on:
• Mast Cells
• Mucociliary Clearance
• Vascular Endothelial Permeability
Mast Cells:
• Reduces Histamine Secretion
Mucociliary Clearance:
• Increase Glycoprotein
• Increase beat frequency of Cilia
Vascular Endothelial Permeability:
• DECREASES Leakage from microvasculature
What is the risk of giving ultra high concentrations of a ß2 agonist?
- CV stimulatory effects
- Prolongation of the QT interval especially in presence of HYPOKALEMIA
- Widening of Pulse Pressure
- DIlation in coronary, pulmonary, and skeletal mm.
How could a ß2 agonist aggravate pre-existing hypokalemia?
- Stimulation of Na+/K+ ATPase in skeletal mm.
- Increased intracellular K+
- Decreased serum K+
*this is why you should avoid giving these with other drugs that cause hypokalemia
What is responsible for the tremor experienced when taking ß2 agonists?
Stimulation of Na+/K+ ATPase activity is responsible for the twitching and tremor seen in people who use these
What are the 5 groups of drugs that you should worry about interacting in someone who is taking a ß2-agonist?
- Tricyclic Antidepressants (TCAs)
- Monoamine Oxidase Inhibitors (MAOIs)
- Saquinavir (HIV drug)
- Loop and Thiazide Diuretics
- Non-specific ß2-blockers
Name two TCAs and explain why they interact with ß2-agonists.
- Amitriptyline and Desipramine
* Block Reuptake of drug and Norepinephrine into nerve terminal
Name two Monoamine oxidase inhibitors and explain why they interact with ß2-agonists.
Selegilene and Rasagilene
• Block Metabolism of amine by Monamine Oxidase-B
Explain why Saquinavir (HIV drug) interacts with ß2-agonists.
- Promotes Hypokalemia
- QT prolongation
- Arrythmias
Explain why loop and Thiazide Diuretics interact with ß2-agonists.
Predispose patient to hypokalemia and INCREASE the likelihood of QT prolongation/arrythmias
• Monitor serum K+ in these ppl.
Why type of GPCR are M1 and M3 receptors?
• M2?
- Gq stimulatory receptors = M1/M3
* Gi/o receptors = M2
Why does overusing an inhaler lead to a loss in potency?
• explain this process.
Internalization of Receptors
• Repeated stimulation => C-terminus phosphorylization of receptor via PKA or ß-adrenergic receptor Kinase (ßARK).
• ß-arrestin binds to phosphorylated domain and blocks Gs binding
• Decrease in Adenylyl Cyclase activity
Genes may also be affected on a long term basis
Why would you give a patient with asthma that doesn’t respond well to albuterol corticosteroids?
Corticosteroids upregulate ß2 receptor transcription
Compare lung permeability to macromolecules and small molecules compared to other portals?
Macromolecules:
• Far more permeable than any other portal
Small Molecules:
• More permeable than small to the GI tract
T or F: small molecules are delivered cleanly via the lung and produce very few metabolite.
True
T or F: no non-invasive route can deliver a drug at the same speed that the respiratory tract can.
True
What opportunistic oral flora might arise in someone who is using an inhaler frequently?
• how can this be attenuated?
- Candidiasis - locally suppressed immune function by corticosteroids allows for it to flourish
- Washing your mouth out after administration or using a spacer device could help with this
What is the problem with acidic powders that are delivered via inhaler?
• how can this be attenuated?
- They may corrode your teeth
* Washing your mouth out after administration or using a spacer device could help with this
Will drugs that are deposited on the tracheal epithelial surface be absorbed quickly?
NO - tracheal thickness = 50-60µm whereas alveolar thickness is around 0.2µm
Would you expect a hydrophobic or hydrophilic drug to be absorbed more rapidly via the respiratory route?
- Lipid Soluble Drugs are absorbed more rapidly because they can diffuse across the epithelium
- Water soluble drugs are likely absorbed paracellularly in which they pass through aqueous pores in the intercelular tight junctions
What is the most important physicochemical property that determines if a small drug can cross the lung epithelium?
• Ionization is the main determinant for molecules between 100 and 1000 D
What 4 general groups of drugs work in the upper respiratory tract?
- Mucolytics
- Vasoconstrictors -> alpha-1 agonists
- Drugs acting in the CNS cough center
- Antihistamines
What are the 2 general kinds of drugs used to treat COPD and Restrictive lung diseases?
• what are some drugs types that fall into these categories?
- Bronchodilators
• Anticholinergic
• Adrenergics
• Adenosine antagonist - Anti-inflammatory
• Corticosteroids
• LTAs
• Adenosine antagoists
What drugs are used in the the treatment of Pulmonary Artery Hypertension?
- Prostanoids
- Endothelin Antagonists
- PDE-5 inhibitors
What drugs are used in the treatment of Cystic Fibrosis?
CTFR potentiators (ivacaftor)
